Abstract Ulcerative colitis (UC)-induced colitis-associated colorectal cancer (CAC) has a worse prognosis than sporadic colorectal cancer. And with the incidence of ulcerative colitis on the rise, it is critical to identify new therapeutic targets in time to stop the progression of inflammation to cancer. Through immunohistochemistry (IHC) and Gene Expression Omnibus (GEO) database analysis, we acquired the gene M2DEG, which is differentially expressed in M2 macrophages. The impact of M2DEG on the immune environment and clinical variables was confirmed through various data sets and actual tissue samples. Our findings indicate that patients with UC exhibiting reduced M2 macrophage infiltration tend to have more widespread disease, elevated endoscopic Mayo scores, and a higher probability of developing CAC. Through examining the string of M2DEG between UC and CAC, THBS2 emerged as a key marker. Elevated levels of THBS2 were notably linked to reduced overall survival (OS) and progression-free survival (RFS), and this heightened THBS2 expression played a crucial role in the spread of tumors, as verified by immunohistochemical studies. To sum up, patients with UC exhibiting reduced M2 macrophage infiltration have a higher propensity for CAC development, making THBS2 a crucial focus for converting UC into CAC. Furthermore, identifying antibody analogues targeting THBS2 could potentially lower the likelihood of CAC transformation in patients with UC. 

Identification of the M2 Macrophage-associated Gene THBS2 as a Predictive Marker for Inflammatory Cancer Transformation

The relationship between disulfidptosis and rheumatoid arthritis (RA) remains unclear. We aimed to identified biomarkers disulfidptosis-related in RA and revealed potential targeted drugs. Two microarray datasets (GSE93272, GSE45291) related to RA were downloaded from the Gene Expression Omnibus (GEO) database. Disulfidptosis-related genes(DRGs) were extracted from FerrDb database. GSE93272 was used to identify DRGs, and GSE45291 was used to verify results. Multivariate Cox regression analysis was used to identify candidate disulfidptosis-associated hub genes. The differentiated values of DRGs were determined by receiver operator characteristic (ROC) monofactor analysis to judge their potential quality as biomarkers. RT-qPCR were used to validate the expression of hub genes. Additionally, we analyzed the connection between the hub genes and the filtration of immune cells in RA. We made predictions about the miRNAs, TFs and possible drugs that regulate the hub genes. Subsequently, molecular docking was carried out to predict the combination of drugs with hub targets. Finally, molecular dynamics simulation was conducted to further verify the findings. Oxoacyl-ACP Synthase Mitochondrial(OXSM) was identified as a biomarker with high diagnostic value, and an RA diagnostic model based on OXSM for a single gene was constructed. The model showed high accuracy in distinguishing RA and healthy controls (AUC = 0.802) and was validated by external datasets, showing excellent diagnostic power (AUC = 0.982). Twelve potential drugs against RA were recognized by comparative toxicogenomics database (CTD). Molecular docking results showed that ICG 001 had the highest binding affinity to OXSM, and molecular dynamics simulations confirmed the stability of this complexes. Furthermore, CIBERSORT analysis showed a significant correlation between immune cell infiltration and OXSM, and a regulatory network of TFs-gene-miRNAs comprising 8 miRNAs and 34 TFs was identified. Finally, the RT-qPCR results showed that OXSM was significantly increased in the peripheral blood of RA patients compared with healthy controls, consistent with the bioinformatics analysis. These studies suggest that OXSM may be a potential biomarker and therapeutic target for diagnosing RA, and ICG 001 may be a potential drug for RA. These findings may provide new avenues for the effective diagnosis and treatment of RA.

Identification biomarkers and therapeutic targets of disulfidptosis-related in rheumatoid arthritis via bioinformatics, molecular dynamics simulation, and experimental validation.

Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis. Extreme myopia (EM) is a leading cause of sight impairment caused by progressive retinal degeneration. Here, the authors perform whole-exome sequencing to investigate rare protein-truncating variants among EM cases and identify KDELR3 which contributes to the pathogenesis of EM.

Exome-wide association study identifies KDELR3 mutations in extreme myopia

Non-coding RNAs (lncRNAs) play critical roles in various cellular processes, including a novel form of regulated cell death known as disulfidptosis, characterized by accumulating protein disulfide bonds and severe endoplasmic reticulum stress. This review highlights the therapeutic potential of lncRNAs in regulating disulfidptosis for cancer treatment, emphasizing their influence on key pathway components such as GPX4, SLC7A11, and PDIA family members. Recent studies have demonstrated that targeting specific lncRNAs can sensitize cancer cells to disulfidptosis, offering a promising approach to cancer therapy. The regulation of disulfidptosis by lncRNAs involves various signaling pathways, including oxidative stress, ER stress, and calcium signaling. This review also discusses the molecular mechanisms underlying lncRNA regulation of disulfidptosis, the challenges of developing lncRNA-based therapies, and the future potential of this rapidly advancing field in cancer research. 

Therapeutic Potential of lncRNAs in Regulating Disulfidptosis for Cancer Treatment

Background Disulfidptosis and ferroptosis are forms of programmed cell death that may be associated with the pathogenesis of periodontitis. Our study developed periodontitis-associated biomarkers combining disulfidptosis and ferroptosis, which provides a new perspective on the pathogenesis of periodontitis. Methods Firstly, we obtained the periodontitis dataset from public databases and found disulfidptosis- and ferroptosis-related differentially expressed transcripts based on the disulfidptosis and ferroptosis transcript sets. After that, transcripts that are tissue biomarkers for periodontitis were found using three machine learning methods. We also generated transcript subclusters from two periodontitis microarray datasets: GSE16134 and GSE23586. Furthermore, three transcripts with the best classification efficiency were further screened. Their expression and classification efficacy were validated using qRT-PCR. Finally, periodontal clinical indicators of 32 clinical patients were collected, and the correlation between three transcripts above and periodontal clinical indicators was analyzed. Results We identified six transcripts that are tissue biomarkers for periodontitis, the top three transcripts with the best classification, and delineated two expression patterns in periodontitis. Conclusions Our study found that disulfidptosis and ferroptosis were associated with immune responses and may involve periodontitis genesis. 

Identification of disulfidptosis- and ferroptosis-related transcripts in periodontitis by bioinformatics analysis and experimental validation

Disulfidptosis is a recently identified form of cell death that contributes to maintaining the internal environment balance of an organism. However, the molecular basis of disulfidptosis in ulcerative colitis (UC), ankylosing spondylitis (AS), and Crohn’s disease (CD) has not been thoroughly explored.Firstly, the differentially expressed genes (DEGs) and disulfidptosis-associated genes (DAGs) were obtained through differential analysis between diseases (AS, CD, and UC) and control groups. After the disulfidptosis score was acquired using the single-sample gene set enrichment analysis (ssGSEA) algorithm, the DE-DAGs were screened by overlapping DAGs and DEGs of the three diseases. Next, the feature genes were selected through a combination of machine learning algorithms, receiver operating characteristic (ROC) curves, and expression analysis. Based on these feature genes, nomograms were created for AS, CD and UC. The co-feature genes were then identified by taking the intersections of the genes featured in all three diseases. Meanwhile, single-gene set enrichment analysis (GSEA) and the TF-mRNA-miRNA network were utilized to investigate the molecular mechanisms of the co-feature genes. To validate the expression differences of the co-feature genes between healthy controls and patients (AS and IBD), RT-PCR was performed. Lastly, mendelian randomization (MR) analysis was utilized to explore the causality between genetic variants of S100A12 with AS, UC and CD.In this study, 11 DE-DAGs were obtained. Functional enrichment analysis revealed their involvement in cytokine production and fatty acid biosynthesis. Latterly, AS/CD/UC -feature genes were derived, and they all had decent diagnostic performance. Through evaluation, the performance of the nomogram was decent for three diseases. Then, 2 co-feature genes (S100A12 and LILRA5) were obtained. The GSEA enrichment results indicated that the co-feature genes were mainly enriched in the cytokine-cytokine receptor interaction and drug metabolism cytochrome P450. As shown by functional experiments, there was a correlation between the mRNA expression of S100A12 with AS, UC and CD. Additionally, a causal connection between S100A12 and IBD was detected through MR analysis.In this study, 2 co-feature genes (S100A12 and LILRA5) were screened, and their functions were investigated in AS, CD and UC, providing a basis for further research into diagnosis and treatment.

Regulation mechanisms of disulfidptosis-related genes in ankylosing spondylitis and inflammatory bowel disease

BACKGROUND
Multiple studies have associated PTGER4 polymorphisms with susceptibility to several autoimmune diseases, particularly ankylosing spondylitis (AS)-a condition strongly linked to the onset of acute anterior uveitis (AAU). Given this association, we investigated whether PTGER4 variants are associated with AAU susceptibility in Chinese populations.


METHODS
To identify PTGER4 disease susceptibility loci, we recruited 904 healthy subjects (AS-AAU-) and 402 AAU patients (AAU+AS-). Genotyping used the MassArray system (iPLEX Gold). SNP allele and genotype frequency differences between groups were assessed with chi-square tests. To account for multiple comparisons, we applied the Bonferroni correction. Additionally, haplotype analysis and stratified analysis were conducted to further explore potential genetic relationships.


RESULTS
The two PTGER4 single nucleotide polymorphisms (SNPs) loci (rs10440635, rs4133101) exhibited no significant correlation with susceptibility to AAU. No significant differences in haplotype frequencies were observed between AAU groups and controls following stratified analysis.


CONCLUSION
Our findings demonstrate that the two loci, rs10440635 and rs4133101 in PTGER4, were not found to be associated with susceptibility to AAU in this population. Specifically, for rs10440635, the odds ratio (OR) was 0.924 (95% CI: 0.757-1.128, p = 0.438), and for rs4133101, the OR was 0.918 (95% CI: 0.777-1.085, p = 0.314). Even after stratifying the analysis by HLA-B27 status, no statistically significant association was observed. To further elucidate the potential role of PTGER4 in these conditions, additional studies with larger sample sizes, broader genetic variants, and more diverse ethnic populations are warranted.contribution of PTGER4 to these diseases.

Lack of Association Between PTGER4 Polymorphisms and Acute Anterior Uveitis in Chinese Population.

Genome-wide association studies analysis has revealed associations between ankylosing spondylitis (AS) and loci on the TBX21 gene across various populations. This study aimed to investigate if there is a connection between a higher risk of AS in a Chinese population and two polymorphism loci on the TBX21 gene. To achieve this, we performed a case-control investigation involving 363 patients with AS and 907 healthy individuals. Genotyping was carried out using the iPLEX Gold genotyping assay. The analysis of genotypes and haplotypes was performed using SPSS 23.0 and SHEsis software. The results revealed no statistically significant correlation between the two specified single-nucleotide polymorphisms of TBX21 (rs11657479 C/T and rs4794067 C/T) and susceptibility to AS. However, upon conducting stratification analysis, our findings demonstrated a significant association between rs11657479 and susceptibility to human leucocyte antigen (HLA)-B27+ AS in allelic (C vs. T: odds ratio [OR] = 1.52, 95%CI = 1.09-2.11, corrected p [pc] = .028), heterozygous (CT vs. TT: OR = 1.63, 95%CI = 1.13-2.34, pc = .016) and dominant (CT + CC vs. TT: OR = 1.60, 95%CI = 1.12-2.28, pc = .018) models. Furthermore, the haplotype rs4794067/C-rs11657479/C of TBX21 was found to increase the risk of HLA-B27+ AS cases. In conclusion, our findings indicate a correlation between TBX21 gene polymorphism and HLA-B27+ AS patients within the Chinese population.

Correlation of TBX21 gene polymorphisms with ankylosing spondylitis in a Chinese population.

Associations between ulcerative colitis (UC) and ankylosing spondylitis (AS) have been observed in multiple studies, but the common etiology of UC and AS remain unknown. Thus, the current research was conducted to investigate the shared genes and relevant mechanisms in UC and AS. GSE87466 and GSE25101 datasets were used to identify DEGs involved in UC and AS, respectively. The clusterProfiler R package was utilized to detect the biological processes of DEGs in UC and AS. The performance of common DEGs in distinguishing UC or AS samples from control ones were evaluated by ROC curves. The miRWalk, Cistrome and TransmiR database were utilized to construct the network of TF-miRNA-diagnostic biomarker. GSEA method and CTD database were used to investigate the common KEGG pathways shared by UC and AS. In addition, CTD database was also used to detect the interaction score between diagnostic biomarkers and diseases associated with UC or AS. Moreover, prospective diagnostic biomarker-targeting drugs were identified using the DGIdb database. A total of 20 common DEGs were obtained by analyzing data in GSE97466 and GSE25101 datasets. ROC curves revealed that GMFG, GNG11, CLEC4D, CMTM2, VAMP5, S100A8, S100A12 and DGKQ may serve as diagnostic biomarkers for the individuals with AS and UC. A network of TF-miRNA-diagnostic biomarker, composed of 212 nodes and 721 edges, was constructed and visualized by Cytoscape software. Toll-like receptor signaling pathway, antigen processing and presentation, allograft rejection, viral myocarditis, pathways in cancer, graft versus host disease and natural killer cell mediated cytotoxicity were identified as common pathways in UC and AS. For the first time, our study identified 8 common key genes and 7 common pathways in UC and AS. These findings may help to clarify the relationship between UC and AS, and provide guidance in the diagnosis and treatment of UC and AS patients. Author Summary Ankylosing spondylitis (AS) and Ulcerative colitis (UC) are two types of autoimmune diseases that often co-occur. The simultaneous onset of both diseases often results in severe clinical manifestations and limited therapeutic efficacy. So there is an urgent need to gain a deeper understanding of the causes of UC and AS in order to develop more effective treatment strategies. In this study, we explored the genes and pathways commonly involved in two diseases, constructed a transcriptional network, and further investigated potential drugs. The discoveries could potentially offer insights into the connection between UC and AS, and assist in identifying and managing patients with UC and AS.

https://www.biorxiv.org/content/biorxiv/early/2023/04/21/2023.04.20.537616.full.pdf

Key common genes and pathways in ulcerative colitis and ankylosing spondylitis based on bioinformatics analysis

Extreme myopia is more susceptible to SOX2 gene than high myopia.

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